Adaptability of skeletal muscle to hormone treatment in relation to gender and aging

The aims of this study were to investigate the expression of myosin isoforms, muscle contractility at the cell level, and changes in these parameters in response to altered hormonal status in aging male and female rodents. In addition, by using mice lacking thyroid hormone receptors (TR[alpha]1 or TR[beta] or TR[alpha]1/[beta]) we tried to improve our understanding of the mechanisms by which thyroid hormone regulates the expression of specific MyHC isoforms via these different nuclear receptors.

The enzyme-histochemical characteristics showed that 4 weeks of l treatment induced a significant decrease in the number of type I fibers and an increase in the number of type IC and IIC fibers in the soleus, irrespective of gender and age. In the EDL, T3 treatment resulted in a significant type IIA to type IIB fiber transition in both young and old female rats, but no changes were observed in the male rats. TR[alpha]1-/- or TR[alpha]1- /-[beta]-/-mice significantly increased the number of type I fibers and decreased type IIA fibers. The proportions of type I and type IIA fibers did not change in TR[beta] -/- mice.

High-sensitive 7% SDS-PAGE analysis of MyHC isoform composition confirmed and extended the enzyme-histochemical results. That is, a significant down-regulation of the type I MyHC and an up-regulation of type IIA MyHC were observed in muscles from hyperthyroid rats, irrespective of gender. However, the upregulation of the IIX MyHC was more pronounced in male than in female rats both at the single-fiber and whole-muscle levels, irrespective of age. The expression of MyHC isoforms in females was more variable than that in males, i.e., type IIAX fibers, type I/IIAX fibers, [alpha] cardiac-like fibers and [alpha] cardiac-like/IIA fibers were found. In the EDL, the age-related type IIB to IIX MyHC isoform switching was found in both male and female rats, i.e., the type IIX MyHC content was higher and the type IIB content lower in old rats of both sexes. In the females, T3 treatment decreased the type IIA MyHC content and increased type IIB MyHC content in both young and old rats. In the males, on the other hand, T3 treatment had no significant influence on the expression of the different fast MyHC isoforms, in spite of the fact that type IIA mRNA has been reported to be downregulated in both males and females. The different expression of MyHCs in the EDL muscle of males and females in response to T3 treatment raises the possibility of a gender-related difference in the translational regulation of MyHC isoforms by thyroid hormone.

At the single-fiber level, an age-related slowing of maximum velocity of unloaded shortening (V0) was observed in the soleus muscle of rats in both genders. Four weeks of T3 treatment induced a stronger upregulation of the fast MyHC IIA, MyLCf1 and MyLCf2 isoforms from soleus muscle fibers in females than in those of males. Concomitantly, the V0 of the pooled fibers was higher in female than in male hyperthyroid rats regardless of animal age in soleus fibers. Further, in the female hyperthyroid rats, V0 of the fibers expressing [beta]/slow (type I) MyHC was significantly higher, compared with those in control rats of both the young and the old; the differences between male and female hyperthyroid soleus muscles are suggested to be related to an interaction of thyroid hormone and sex hormones in the regulation of myosin gene expression.

Disuption of thyroid hormone receptors TR[alpha]1 or TR[beta] or both receptors induced transitions of MyHC isoforms; i.e., in EDL muscle, the TR deficiency induced a significant decrease in type IIB MyHC. In the soleus, a significant up-regulation of type I MyHC and a down-regulation of type IIA MyHC were observed in TR[alpha]1-/-[beta]-/- and TR[alpha]1-/- mice. The extent of the deficient effect was highly dependent on the type of receptor deleted. The lack of TR[beta] had no significant effect on the expression of MyHC isoforms. A moderate type I MyHC increase was observed in the TR[alpha]1-/-mice, while a dramatic over-expression of the slow myosin isoform (type I MyHC), and a corresponding down-regulation of the fast type IIA MyHC were observed in TR[alpha]1-/-[beta]-/- mice. Embryonic or fetal MyHC isoforms were not expressed in either soleus or EDL from different TR deficient mice, indicating that the developmental transition from embryonic or fetal MyHC isoforms is not solely related to an effect of T3 via TRs. These results suggest that either TR[alpha]1 or TR[beta] is able to functionally substitute for, or co-operate with, each other, and emphasize the complex interaction between TRs and other cell- and muscle-type specific factors, which play a very important role in the developmental transition from embryonic or fetal MyHC to adult MyHC isoforms.